Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the invention relates to new 10-halo-E-homoeburnane derivatives of the formula (I), ##STR3## wherein R 2 is a C 1-6 alkyl group and X is a halogen, and pharmaceutically acceptable acid addition salts, epimers and optically active derivatives thereof.
• the invention also relates to pharmaceutical compositions which contain at least one of the new compounds defined above, and to a process for the preparation of the new compounds and the pharmaceutical compositions.
• the new compounds defined above are prepared according to the invention in that a racemic or optically active 9-halo-octahydroindoloquinolizine derivative of the general formula (II), ##STR4## wherein R 2 and X are as defined above and R 1 is a C 1-6 alkyl group, or an acid addition salt thereof is treated with a strong base, and, if desired, the 15-epimers of the resulting compound having the formula (I) are separated from each other, and/or, if desired, the resulting substance is converted into its pharmaceutically acceptable acid addition salt and/or resolved.
• a racemic or optically active 9-halo-octahydroindoloquinolizine derivative of the general formula (II), ##STR4## wherein R 2 and X are as defined above and R 1 is a C 1-6 alkyl group, or an acid addition salt thereof is treated with a strong base, and, if desired, the 15-epimers of the resulting compound having the formula (
• the new compounds according to the invention possess valuable vasodilating effects, and they can also be utilized as intermediates in the preparation of other pharmaceutically active compounds, such as 10-halovincaminic acid esters.
• R 1 and R 2 can represent a straight-chain or branched C 1-6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl group.
• R 2 represents preferably an ethyl or n-butyl group.
• X may represent all the four halogens, i.e. fluorine, chlorine, bromine and iodine, preferably bromine.
• the starting substances of the formula (II), where X, R 1 and R 2 are as defined above, can be prepared as follows; a 9-halo-1,2,3,4,6,7-hexahydroindolo[2,3-a]quinolizine derivative is reacted with a 2-acyloxy-acrylic acid ester, and the resulting 1-(2'-acyloxy-2'-alkoxycarbonylethyl)-9-halo-1,2,3,4,6,7-hexahydroindolo[2,3-a]quinolizine derivative is first reduced and then deacylated, or first deacylated and then reduced.
• alkali metal hydrides such as sodium hydride
• alkali metal alcoholates such as sodium methoxide, sodium ethoxide, sodium tert.-butoxide and potassium tert.-butoxide
• alkali metal amides such as sodium amide and potassium amide
• alkali metal dialkylamides such as lithium diisopropylamide.
• This treatment can be performed in an inert aprotic non-polar organic solvent, such as an aromatic hydrocarbon (e.g. benzene, toluene or xylene).
• an aromatic hydrocarbon e.g. benzene, toluene or xylene.
• the starting substance is treated with the alkali preferably at or close to the boiling point of the solvent used.
• the above reaction yields the compounds of the formula (I) as mixtures of 15-epimers.
• the individual epimers can be separated from each other preferably by preparative layer chromatography.
• the compounds of the formula (I) are to be converted later into 10-halovincaminic acid esters, the epimers need not be separated, since the subsequent reactions involve the elimination of the center of asymmetry in position 15.
• the compounds of the formula (I) can be reacted with various acids to form the respective acid addition salts.
• acids applicable in the salt formation step, e.g. the following are to be mentioned: mineral acids, such as hydrogen halides (e.g. hydrochloric acid or hydrogen bromide), sulfuric acid, phosphoric acid, nitric acid, perhaloic acids (such as perchloric acid), organic carboxylic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, phenylacetic acid, p-aminosalicylic acid, p-aminobenzoic acid, p-hydroxybenzoic acid; alkylsulfonic acids, such as methanesulfonic acid; ethanesulfonic acid, cycloaliphatic sulfonic acids, such as cyclohexyls
• racemic compounds of the general formula (I) can be resolved in a manner known per se to obtain the respective optically active derivatives.
• the optically active end-products can also be prepared, however, from the appropriate optically active starting substances.
• racemic or optically active compounds of the formula (I) as well as the respective pure epimers and acid addition salts thereof can be subjected to further purification steps, such as recrystallization from an appropriately selected solvent or solvent mixture.
• the solvents or solvent mixtures utilized in this step are chosen in accordance with the solubility and crystallization characteristics of the substance to be purified.
• the process of the invention yields the end-products in forms easy to identify.
• the analytical data, IR spectra, NMR spectra and mass spectra of the compounds prepared are in harmony with the assigned structures.
• the compounds of the formula (I) were subjected to pharmacological tests in order to determine their effects on the circulation.
• the tests were performed on dogs narcotized with chloralose urethane, and the arterial blood pressure, heart rate, and the blood flows in the arteria femoralis and arteria carotis interna were measured.
• Vascular resistances were calculated for the latter two vascular beds by the formula ##EQU1##
• the substances under examination were administered as aqueous solutions in intravenous dosages of 1 mg/kg body weight.
• the tests were repeated five or six times. The results of the tests are listed in Table 1, whereas the corresponding properties of vincamine (reference substance) are given in Table 2.
• MABP mean arterial blood pressure (mmHg)
• CBF blood flow in the carotis interna (ml.min -1 )
• CVR carotis vascular resistance (mm Hg.min.ml -1 )
• FBF femoral blood flow (ml.min -1 )
• FVR femoral vascular resistance (mm Hg.min.ml -1 )
• 10-bromo-14-oxo-15-hydroxy-E-homoeburnane-(3 ⁇ ,17 ⁇ ) hardly affects the blood pressure and the heart rate when administered to narcotized dogs in an intravenous dosage of 1 mg/kg body weight, i.e. it exerts favorably weak effects on the systemic circulation.
• the main effect of 10-bromo-14-oxo-15-hydroxy-E-homoeburnane-(3 ⁇ ,17 ⁇ ) is the dilatation of arteria carotis, which may reach 25%, corresponding to a 21% increase in blood flow. It is particularly advantageous that this compound exerts practically no other effect on the circulation.
• the compounds according to the invention can be applied to advantage in therapy.
• the new compounds according to the invention can be converted into pharmaceutical compositions for parenteral or enteral administration, utilizing conventional non-toxic, inert, solid or liquid pharmaceutical carriers, diluents and/or auxiliary agents.
• pharmaceutical carriers e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, stearic acid, talc and vegetable oils such as peanut oil, olive oil, etc.
• carrier e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, stearic acid, talc and vegetable oils such as peanut oil, olive oil, etc.
• the pharmaceutical compositions can be presented in conventional forms, e.g.
• solids round or angular tablets, coated tablets, capsules, such as hard gelatine capsules, furthermore pills, suppositories, etc.
• liquids such as oily or aqueous solutions, suspensions, emulsions syrups, soft gelatine capsules, injectable oily or aqueous solutions or suspensions, etc.
• the amount of the solid carrier present may vary within wide limits; the solid compositions may contain preferably about 25 mg to 1 g of a carrier.
• the pharmaceutical compositions may also contain conventional pharmaceutical additives, such as preservatives, wetting agents, emulsifying agents, salts for adjusting the osmotic pressure, buffers, flavoring agents, odorants, etc.
• compositions may also contain other known pharmaceutically active substances in addition to the new compounds according to the invention.
• the pharmaceutical compositions are presented preferably in the form of unit dosages corresponding to the way of administration.
• the pharmaceutical compositions are prepared by methods well known in the pharmaceutical industry, such as sieving, mixing, granulating and pressing the components, dissolving the substances, etc. If desired, the compositions can also be subjected to other conventional pharmacotechnical operations, such as sterilization.
• the epimers are separated from the epimeric mixture by preparative thin layer chromatography. Kieselgel PF 254+366 grade silica gel plates, 20 ⁇ 20 cm in area and 1.5 mm in thickness, are applied as adsorbent, and a 14:3 mixture of benzene and methanol is utilized as solvent. The product is eluted with dichloromethane.
• the fast-moving epimer is termed as epimer "A”
• epimer "B" is crystallized from 10 ml of methanol.

Applications Claiming Priority (2)

Publications (1)

Family

ID=11001106

Family Applications (1)

Country Status (23)

Cited By (2)

Families Citing this family (4)

Citations (2)

Family Cites Families (4)

• 1979
  • 1979-08-13 HU HU79RI723A patent/HU181496B/hu not_active IP Right Cessation
• 1980
  • 1980-07-14 DE DE19803026584 patent/DE3026584A1/de not_active Withdrawn
  • 1980-07-22 PH PH24325A patent/PH16023A/en unknown
  • 1980-07-25 BE BE1/9906A patent/BE884472A/fr not_active IP Right Cessation
  • 1980-08-05 US US06/175,383 patent/US4285950A/en not_active Expired - Lifetime
  • 1980-08-11 GB GB8026072A patent/GB2058759B/en not_active Expired
  • 1980-08-12 AU AU61370/80A patent/AU541869B2/en not_active Ceased
  • 1980-08-12 CA CA000358098A patent/CA1140121A/en not_active Expired
  • 1980-08-12 NZ NZ194654A patent/NZ194654A/xx unknown
  • 1980-08-12 SU SU802957550A patent/SU993819A3/ru active
  • 1980-08-12 DK DK348080A patent/DK154431C/da not_active IP Right Cessation
  • 1980-08-12 SE SE8005687A patent/SE436881B/sv not_active IP Right Cessation
  • 1980-08-12 NL NL8004565A patent/NL8004565A/nl not_active Application Discontinuation
  • 1980-08-12 NO NO802403A patent/NO153730C/no unknown
  • 1980-08-12 JP JP10989380A patent/JPS5629590A/ja active Granted
  • 1980-08-12 AT AT0412780A patent/AT375940B/de not_active IP Right Cessation
  • 1980-08-12 FR FR8017733A patent/FR2463141A1/fr active Granted
  • 1980-08-12 FI FI802535A patent/FI67382C/fi not_active IP Right Cessation
  • 1980-08-12 ZA ZA00804922A patent/ZA804922B/xx unknown
  • 1980-08-12 IL IL60827A patent/IL60827A/xx unknown
  • 1980-08-12 CH CH608480A patent/CH644123A5/de not_active IP Right Cessation
  • 1980-08-13 ES ES494211A patent/ES494211A0/es active Granted
  • 1980-08-13 IT IT24151/80A patent/IT1132404B/it active

Patent Citations (2)

Also Published As

Similar Documents

Legal Events